Shifting the Focus of Preclinical, Murine Atherosclerosis Studies From Prevention to Late-Stage Intervention.

Abstract

Could improving the design of preclinical murine atherosclerosis studies help increase the success rate of cardiovascular clinical trials? In this Viewpoint, the authors advocate for a change from prevention to intervention study designs and rigorous lesion analyses that they argue will enhance the translational potential of murine atherosclerosis studies. Clinical management of patients with coronary artery disease (CAD) has made great progress by reducing risk factors like low-density lipoprotein cholesterol level, hypertension, and diabetes mellitus. However, late-stage events associated with coronary atherosclerosis including myocardial infarction still account for ≈16% of worldwide mortality and are forecasted to increase in prevalence.1 These events arise from 3 main processes: plaque rupture, plaque erosion, and shedding of calcific nodules. Plaque rupture accounts for the majority of CAD and typically occurs in vulnerable atherosclerotic lesions termed thin-capped fibroatheromas,2 characterized by thin fibrous caps (<65 µm) with high numbers of CD68+ macrophages relative to Acta2+ smooth muscle cells (SMC), large lipid-rich necrotic cores, and often evidence of intraplaque hemorrhage. Much of the difficulty in therapeutically targeting atherosclerosis can be attributed to (1) the nearly ubiquitous prevalence of atherosclerosis development; (2) the slow, clinically-silent progression but acute and often catastrophic presentation of symptoms; and (3) most importantly, the difficulty in identifying patients at high risk for plaque rupture or erosion and subsequent cardiovascular events. Therefore, clinical trials seeking to investigate novel CAD therapies are forced to enroll thousands of patients who already have manifestations of advanced CAD and spend hundreds of millions of dollars to conduct adequately powered phase III clinical trials to rigorously test therapeutic efficacy. And yet, cardiovascular disease trials have one of the lowest success rates of the major medical fields.3 Perhaps, the lack of success can, in part, be attributed to suboptimal design of preclinical studies, which commonly …